Inflammatory Bowel Disease
The term inflammatory bowel disease (“IBD”) describes a group of chronic inflammatory disorders of unknown causes in which the intestine (bowel) becomes inflamed, often causing recurring cramps or diarrhea. IBD is generally divided into ulcerative colitis (UC) and Crohn's disease. In UC, the inflammatory response is confined to the mucosa and submucosa of the colon with clear demarcations. In Crohn's disease, the entire gastrointestinal tract can be involved and the inflammation can extend through the intestinal wall from mucosa to serosa. Areas of inflammation may be interspersed with relatively normal mucosa. In Crohn's disease, the predominant symptoms are diarrhea, abdominal pain and weight loss whereas in UC diarrhea is the main symptom, often accompanied by rectal bleeding. Both diseases are common in the industrialized world, with highest incidences in North America and Northern Europe (Russel et al., Scand J Gastroenterol 1996; 31: 417-27). In a European study, the average annual incidence was 5.9/100,000 for Crohn's disease and 11.2/100,000 for UC (Shivananda et al., Gut 1996; 39: 690-7). The peak age of onset for both diseases is between 15 and 30 years with a second minor peak between 55 and 80 years. Crohn's disease shows a higher incidence in females than in males. UC seems more equally distributed between the sexes, with a tendency to a male preponderance.
Clinically, IBD is characterized by diverse manifestations often resulting in a chronic, unpredictable course. Bloody diarrhea and abdominal pain are often accompanied by fever and weight loss. Anemia is not uncommon, as is severe fatigue. Joint manifestations ranging from arthralgia to acute arthritis as well as abnormalities in liver function are commonly associated with IBD. Patients with IBD also have an increased risk of colon carcinomas compared to the general population. During acute “attacks” of IBD, work and other normal activity are usually impossible, and often a patient is hospitalized. A detailed description of IBD symptoms and sequelae is found in, for example, Northfield, Drugs, Vol. 14, pages 198-206 (1977); Blaker et al, Eur. J. Pediatr., Vol. 139, pages 162-164 (1982); Singleton, The Gastroenterology Annual, pages 268-310 (1983); Saco et al, J. Amer. Acad. Dermatol., Vol. 4, pages 619-629 (1981); Prantera et al, Ital. J. Gastroenterol., Vol. 13, pages 24-27 (1981); Sales et al, Arch. Int. Med., Vol. 143, pages 294-299 (1983); and Ament, Inflammatory Bowel Diseases, Martinus Nijhoff Publ., Boston, Mass., pages 254-268 (1982).
Although the cause of IBD remains unknown, several factors such as genetic, infectious, and immunologic susceptibility have been implicated. IBD is much more common in Caucasians, especially those of Jewish descent. The chronic inflammatory nature of the condition has prompted an intense search for a possible infectious cause. Although agents have been found which stimulate acute inflammation, none has been found to cause the chronic inflammation associated with IBD. The hypothesis that IBD is an autoimmune disease is supported by the previously mentioned extraintestinal manifestation of IBD as joint arthritis, and the known positive response to IBD by treatment with therapeutic agents such as adrenal glucocorticoids, cyclosporine and azathioprine, which are known to suppress immune responses. In addition, the GI tract more than any other organ of the body, is continuously exposed to potential antigenic substances such as proteins from food, bacterial byproducts (LPS), etc.
Diarrheal diseases remain a major global health problem, particularly among children under 5 years of age. Among the most important pathogens causing diarrhea are Shigella spp and diarrheagenic E. coli pathotypes (Moore S R Curr Opin Gastroenterol, Kaper J B, Nataro J P, & Mobley H L (2004) Nat Rev Microbiol 2, 123-140. 3. O'Ryan M, Prado V, & Pickering L K (2005) Semin Pediatr Infect Dis 16, 125-136). In aggregate, these pathogens are estimated to cause more than 1 million deaths per year. Despite their importance as agents of human disease, there remain many unanswered questions regarding the pathogenetic mechanisms of these microorganisms, and there are no licensed vaccines for any of these agents. One potential obstacle to the use of attenuated pathogens as enteric vaccines is the possibility that they may exhibit as yet undiscovered mechanisms of immune suppression.
Once a diagnosis of IBD has been made, typically by endoscopy, the goals of therapy are to induce and maintain a remission. The least toxic agents which patients are typically treated with are the aminosalicylates. Sulfasalazine (Azulfidine), typically administered four times a day, consists of an active molecule of aminosalicylate (5-ASA) which is linked by an azo bond to a sulfapyridine. Anaerobic bacteria in the colon split the azo bond to release active 5-ASA. However, at least 20% of patients cannot tolerate sulfapyridine because it is associated with significant side-effects such as reversible sperm abnormalities, dyspepsia, or allergic reactions to the sulpha component. These side effects are reduced in patients taking olsalazine. However, neither sulfasalazine nor olsalazine are effective for the treatment of small bowel inflammation. Other formulations of 5-ASA have been developed which are released in the small intestine (e.g. mesalamine and asacol). Normally it takes 6-8 weeks for 5-ASA therapy to show full efficacy. Patients who do not respond to 5-ASA therapy, or who have a more severe disease, are prescribed corticosteroids. However, this is a short term therapy and cannot be used as a maintenance therapy. Clinical remission is achieved with corticosteroids within 2-4 weeks, however the side effects are significant and include a Cushing goldface, facial hair, severe mood swings, and sleeplessness. The response to sulfasalazine and 5-aminosalicylate preparations is poor in Crohn's disease, fair to mild in early ulcerative colitis and poor in severe ulcerative colitis. If these agents fail, powerful immunosuppressive agents such as cyclosporine, prednisone, 6-mercaptopurine or azathioprine (converted in the liver to 6-mercaptopurine) are typically tried. For Crohn's disease patients, the use of corticosteroids and other immunosuppressives must be carefully monitored because of the high risk of intra-abdominal sepsis originating in the fistulas and abscesses common in this disease. Approximately 25% of IBD patients will require surgery (colectomy) during the course of the disease.
Further, the risk of colon cancer is elevated in patients with severe ulcerative colitis, particularly if the disease has existed for several years. About 20-25% of patients with IBD eventually require surgery for removal of the colon because of massive bleeding, chronic debilitating illness, performation of the colon, or risk of cancer. Surgery is also sometimes performed when other forms of medical treatment fail or when the side effects of steroids or other medications threaten the patient's health. As surgery is invasive and drastically life altering, it is not a highly desirable treatment regimen, and is typically the treatment of last resort.
Airway Inflammation
Inflammation of the airway encompasses widespread conditions with complex and multifactorial etiologies. The severity of the conditions vary widely between individuals, and within individuals, dependent on factors such as genetics, environmental conditions, and cumulative respiratory tract pathology associated with duration and severity of disease. Airway inflammation can be the result of immune system hyper-responsiveness to innocuous environmental antigens, with asthma typically including an atopic (i.e., allergic) component.
In asthma, the pathology manifests as inflammation, mucus overproduction, and reversible airway obstruction that may result in scarring and remodeling of the airways. Mild asthma is relatively well controlled with current therapeutic interventions including beta-agonists and low dose inhaled corticosteroids or cromolyn. However, moderate and severe asthma are less well controlled, and require daily treatment with more than one long-term control medication to achieve consistent control of asthma symptoms and normal lung function. With moderate asthma, doses of inhaled corticosteroids are increased relative to those given to mild asthmatics, and/or supplemented with long acting beta-agonists (LABA) (e.g., salmeterol) or leukotriene inhibitors (e.g., montelukast, zafirlukast). Although LABA can decrease dependence on corticosteroids, they are not as effective for total asthma control as corticosteroids (e.g., reduction of episodes, emergency room visits) (Lazarus et al., JAMA. 2001. 285: 2583-2593; Lemanske et al., JAMA. 2001. 285: 2594-2603). With severe asthma, doses of inhaled corticosteroids are increased, and supplemented with both LABA and oral corticosteroids. Severe asthmatics often suffer from chronic symptoms, including nighttime symptoms, limitations on physical activities, and more frequent emergency room visits. Additionally, chronic corticosteroid therapy at any level has a number of unwanted side effects, especially in children (e.g., damage to bones resulting in decreased growth.
Allergic and non-allergic rhinitis and sinusitis is a form of airway inflammation that affects the nasal passages, and is typically associated with watery nasal discharge, sneezing, congestion and itching of the nose and eyes. It is frequently caused by exposure to irritants, particularly allergens. Allergic rhinitis and sinusitis affects about 20% of the American population and ranks as one of the most common illnesses in the US. Most suffer from seasonal symptoms due to exposure to allergens, such as pollen, that are produced during the natural plant growth season(s). A smaller proportion of sufferers have chronic allergies due to allergens that are produced throughout the year such as house dust mites or animal dander. A number of over the counter treatments are available for the treatment of allergic rhinitis and sinusitis, including oral and nasal antihistamines and decongestants. Antihistamines are utilized to block itching and sneezing and many of these drugs are associated with side effects such as sedation and performance impairment at high doses. Decongestants frequently cause insomnia, tremor, tachycardia, and hypertension. Nasal formulations, when taken improperly or terminated rapidly, can cause rebound congestion. Anticholinergics and montelukast have substantially fewer side effects, but they also have limited efficacy. Similarly, prescription medications are not free of side effects. Nasal corticosteroids can be used for prophylaxis or suppression of symptoms; however, compliance is variable due to side effects including poor taste and nasal irritation and bleeding. Allergen immunotherapy is expensive and time consuming and carries a risk of anaphylaxis.
Despite the advances in the treatment for IBD and airway inflammation, there is no cure for either and current therapies have certain limitations and drawbacks. Therefore, there is an unmet need in the medical arts for treating IBD, airway inflammation, cancer and other inflammatory disorders.